ABSTRACT Parkinson's disease (PD) is the 2nd most common neurodegenerative disorder, affecting over 1 million people in the United States. PD causes difficulties with movements such as walking and speaking that occur because of loss of the brain chemical dopamine. Current symptomatic PD treatments are based largely on dopamine replacement therapies with L-DOPA; however, these treatments have many long-term side effects which led to interest in non-dopaminergic therapies. The most severe side effect is the development of L-DODA-induced dyskinesia (LID), involuntary movements that can be as or even more debilitating than the disease itself. Any adjunct therapy extending the time frame where L-DOPA can be used without LID would be a major advance. Recent publications showed that low-dose ketamine infusion paradigms were safe and well tolerated in clinical trials for pain states (including migraine headaches), treatment-resistant depression and posttraumatic stress disorder (PTSD). Low-dose ketamine has led to a long-term reduction of pain states, treatment-resistant depression, it also reduced PTSD symptom severity and comorbid depression. One commonality between migraine headaches, depression, PTSD, PD and LID is that electric activity in the brain is overly synchronized and maladaptive plastic changes occur in the brain, including in an area that is of interest in PD and LID called the basal ganglia (BG). Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of PD and LID. We have evidence of a therapeutic effect of low-dose ketamine infusion from preclinical data in a rat model of LID (dose-dependent reduction of abnormal involuntary movements; long-term effects after a single ?infusion-treatment?) and from 5 PD patient case studies (reduced dyskinesia and reduced depression). In the rat LID model this effect was only seen when low-dose ketamine was given for 10 hours and not with just a single acute low-dose ketamine injection. The premise of the proposed studies to define mechanisms of the novel use of low-dose ketamine is ?true bench to bedside? science, will provide the foundation for controlled clinical trials of low-dose ketamine treatment for LID, and could identify new more specific therapeutic drug targets to treat LID and depression, two critical problems for many PD patients. Our main hypothesis is that a low-dose sub-anesthetic ketamine infusion desynchronizes overly synchronous oscillatory activity in nerve cells involved in LID sufficiently to induce a lasting anti-dyskinetic effect, working as a ?chemical deep brain stimulation (DBS)?. We hypothesize that ketamine works on the molecular level via 2 types of receptor molecules in the BG and cortex, NMDA receptors and opioid receptors, and that the long-term effect includes changes in nerve cell connections called dendritic spines. A multidisciplinary team of researchers and a clinician with the necessary expertise will fill a critical gap in knowledge by investigating the mechanisms of this long-term effect of low-dose ketamine infusion on the molecular and cellular level. They will study effects on receptors and changes in spine size and density (Aim 1), and on the systems level, investigate synchrony of oscillatory neural activity (Aim 2).